The majority of the HIV/AIDS pandemic resides in developing countries where HIV-1 non-B (particularly subtype C) subtypes predominate. Our understanding of the virological determinants governing rates of disease progression will be enhanced by investigating host-virus relationships that may account for potential differences among subtype C infections in India and South Africa. We propose to assess viral cytopathicity in 3 experimental systems: (1) in vitro kinetics and CD4+ T lymphocyte depletion by FACS analysis; (2) ex vivo culture of tonsilar histocultures; and (3) SCID-hu thy/liv model. The specific role that the viral envelope (gp120) plays in co-receptor signaling, apoptosis, and CD4+ T lymphocyte depletion will be investigated. Preliminary analysis of viral phenotypes has demonstrated phenotypic differences among a panel of subtype C/R5 seroconvertor isolates by replication kinetics on unstimulated and anti-CD3/IL-2 stimulated PBMC. In addition, we have assessed the cytopathic properties of CCR5 and CXCR4 tropic HIV-1 isolates of subtypes B, C and E origin and have found that despite differences in viral subtype, co-receptor preference was the primary factor in rates of CD4+ T cell depletion. We are now investigating the role that various host factors play in determining rates of disease progression in non-B subtype infections. Our investigations will focus on polymorphisms that have established relationships with known disease outcomes, as well as novel or newly identified genotypes that have been shown to be associated with either protection or acceleration of disease progression. The ultimate goal of this work will be to determine the nature of the host-pathogen relationship and its correlation with disease outcomes in HIV-1 non-B subtype infections in non-Western cohorts.